Human immunodeficiency virus (HIV) isolated from patients treated with zidovudine (AZT) may demonstrate markedly reduced in vitro susceptibility to AZT (Larder et al., 1989, Science 243:1731-1734; Rooke et al., 1989, AIDS 3:411-415; Land et al., 1990, J. Infect. Dis. 161:326-329; Boucher et al., 1990, Lancet 336:585-590; Japour et al., 1991, Proc. Natl. Acad. Sci. 88:3092-96; Tudor-Williams et al., 1992, Lancet 339:15-19). This reduced susceptibility has been related to the duration of therapy with AZT and the severity of HIV disease at the time AZT therapy is begun (Richman et al., 1990, AIDS 3:743-756). Nucleotide sequence analysis of AZT-resistant HIV strains has revealed a number of mutations in the reverse transcriptase (RT) gene associated with decreased AZT susceptibility (Larder et al., 1989, Science 246:1155-1158; Larder et al., 1991, AIDS 5:4137-144; Kellam et al., 1992, Proc. Natl. Acad. Sci. USA 89:1934-1938; St. Clair et al., 1991, Science 253:1557-1559; Richman et al., 1991, J. Infect. Dis. 164:1075-1081). Molecular cloning experiments have confirmed that these mutations in the RT gene confer AZT resistance (Larder et al., 1989, Science 246:1155-1158; Larder et al., 1991, AIDS 5:137-144; Kellam et al., 1992, Proc. Natl. Acad. Sci. USA 89:1934-1938; St. Clair et al., 1991, Science 253:1557-1559). Of these mutations the one at codon 215 resulting in a single amino acid substitution (Thr.fwdarw.Tyr or Phe) has been shown to be the most common mutation and to have the greatest impact on in vitro susceptibility to AZT (Larder et al., 1991, AIDS 5:137-144; Richman et al., 1991, J. Infect. Dis. 164:1075-1081; Boucher et al., 1992, J. Infect. Dis. 165:105-110).
Several studies have addressed the relationship between in vitro AZT resistance, mutations in the RT gene and clinical disease. Richman and coworkers studied 32 patients with different stages of HIV disease and demonstrated that the development of in vitro AZT resistance was related to the duration of therapy with AZT and to the severity of disease at the time AZT was begun (Richman et al., 1990, AIDS 3:743-746). Boucher and coworkers studied HIV P24-antigenemic patients treated with AZT for 2 years. They observed that at 6 months, seven patients with a mutation at codon 215 had a weak, non-statistically significant trend toward lower CD4 counts compared to nine patients who were wild type at codon 215 (Boucher et al., 1990, Lancet 336:585-590). After 2 years nearly all patents had the mutation. Tudor-Williams and coworkers studied HIV isolates from 19 symptomatic children treated with AZT for 9-39 months and showed that in vitro AZT resistance was associated with poor clinical outcome (Tudor-Williams et al., 1992, Lancet 339:15-19).
Kahn and colleagues (Kahn et al., 1992, N. Engl. J. Med. 327:581-587) reported that patients infected with HIV who have relatively advanced disease and at least 16 weeks of previous zidovudine therapy may have clinical benefit if switched to didanosine monotherapy instead of remaining on zidovudine. The reason patients benefit from switching from zidovudine to didanosine is not fully understood, but one possibility is that dididanosine is suppressing zidovudine-resistant HIV.
Increasing evidence exists of a correlation between zidovudine-resistant HIV and disease progression in patients treated with zidovudine monotherapy (Tudor-Williams et al., 1992, Lancet 339:15-19; St. Clair et al., 1993, AIDS 6:891-897; Kozal et al., 1993, J. Infect. Dis. 167:526-532; Montaner et al., 1993, AIDS 7:189-196). It has been shown that HIV can also develop resistance to didanosine (ddI)(St. Clair et al., 1991, Science 253:1557-1559; Reichman et al., 1993, Antiviral Res. 20:267-277; Japour et al., 1991, Proc. Natl. Acad. Sci. USA 88:3092-3096). As with the resistance of HIV to zidovudine, the decrease in susceptibility of HIV to didanosine has been shown to be caused by specific mutations in the HIV reverse-transcriptase gene. St. Clair and colleagues (St. Clair et al., 1991, Science 253:1557-1559) identified the first mutation in the reverse-transcriptase gene to confer resistance to didanosine, a mutation at codon 74 that results in an amino acid change from leucine to valine. The codon 74 mutation in an HIV construct can induce an eightfold decrease in susceptibility to didanosine.
Although other mutations have been reported to confer didanosine resistance (Gu et al., 1992, J. Virol. 66:28-35), most data to date suggest the codon 74 mutation is the primary mutation responsible for didanosine resistance in patients receiving didanosine monotherapy.